Soria Jean-Charles, Rodriguez Marivonne, Liu Diane D, Lee J Jack, Hong Waun Ki, Mao Li
Molecular Biology Laboratory, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Cancer Res. 2002 Jan 15;62(2):351-5.
Promoter hypermethylation plays an important role in the inactivation of tumor suppressor genes during tumorigenesis. Recent data suggest that such epigenetic abnormality may occur very early in lung carcinogenesis. To determine the extent of promoter hypermethylation in early lung tumorigenesis, we analyzed promoter methylation status of the p16, death-associated protein kinase (DAPK) and glutathione S-transferase P1 (GSTP1) genes using methylation-specific PCR in bronchial brush samples obtained from 100 former smokers enrolled in a chemoprevention clinical trial. We found that 17% of the samples showed methylation for p16 and 17% the same for DAPK, whereas only 6% of the samples displayed methylation for GSTP1. A total of 32% of the samples had methylation in at least one of the three genes tested, and 8% of the samples had methylation in two genes. The methylation status of p16 was correlated with that of DAPK (P = 0.04, Fisher's exact test). p16 methylation was higher in former smokers with a history of previous cancer than in former smokers without a history of cancer (P = 0.04, Fisher's exact test), and methylation of DAPK was detected more frequently in older patients than it was in younger patients (P = 0.01, Wilcoxon rank-sum test). Surprisingly, no correlation was found between methylation in any of these genes and the smoking characteristics of the individuals analyzed (packs per day, pack-years, smoking years, quitting years). The precise meaning of methylated genes in the bronchial brush samples of former smokers must be sought by means of careful follow-up of these individuals.
启动子高甲基化在肿瘤发生过程中肿瘤抑制基因的失活中起重要作用。最近的数据表明，这种表观遗传异常可能在肺癌发生的早期就出现。为了确定早期肺癌发生中启动子高甲基化的程度，我们使用甲基化特异性PCR分析了100名参加化学预防临床试验的既往吸烟者支气管刷检样本中p16、死亡相关蛋白激酶（DAPK）和谷胱甘肽S-转移酶P1（GSTP1）基因的启动子甲基化状态。我们发现17%的样本显示p16甲基化，17%的样本显示DAPK甲基化，而只有6%的样本显示GSTP1甲基化。总共32%的样本在至少一个检测的三个基因中存在甲基化，8%的样本在两个基因中存在甲基化。p16的甲基化状态与DAPK的甲基化状态相关（P = 0.04，Fisher精确检验）。有既往癌症史的既往吸烟者中p16甲基化高于无癌症史的既往吸烟者（P = 0.04，Fisher精确检验），DAPK甲基化在老年患者中的检测频率高于年轻患者（P = 0.01，Wilcoxon秩和检验）。令人惊讶的是，在这些基因中的任何一个的甲基化与所分析个体的吸烟特征（每天吸烟包数、吸烟包年数、吸烟年数、戒烟年数）之间未发现相关性。必须通过对这些个体的仔细随访来探寻既往吸烟者支气管刷检样本中甲基化基因的确切意义。
